A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease.

The reabsorption of uric acid (UA) is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidneys. Dotinurad inhibits URAT1 but does not inhibit other UA transporters, such as GLUT9, ATP-binding cassette transporter G2 (ABCG2), and organic anion transporter 1/3 (OAT1/3). We found that dotinurad ameliorated the metabolic parameters and renal function in hyperuricemic patients. We consider the significance of the highly selective inhibition of URAT1 by dotinurad for metabolic syndrome, chronic kidney disease (CKD), and cardiovascular disease (CVD). The selective inhibition of URAT1 by dotinurad increases urinary UA in the proximal tubules, and this un-reabsorbed UA may compete with urinary glucose for GLUT9, reducing glucose reabsorption. The inhibition by dotinurad of UA entry via URAT1 into the liver and adipose tissues increased energy expenditure and decreased lipid synthesis and inflammation in rats. Such effects may improve metabolic parameters. CKD patients accumulate uremic toxins, including indoxyl sulfate (IS), in the body. ABCG2 regulates the renal and intestinal excretion of IS, which strongly affects CKD. OAT1/3 inhibitors suppress IS uptake into the kidneys, thereby increasing plasma IS, which produces oxidative stress and induces vascular endothelial dysfunction in CKD patients. The highly selective inhibition of URAT1 by dotinurad may be beneficial for metabolic syndrome, CKD, and CVD.

Metabolic-Dysfunction-Associated Steatotic Liver Disease-Its Pathophysiology, Association with Atherosclerosis and Cardiovascular Disease, and Treatments.

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease that affects more than a quarter of the global population and whose prevalence is increasing worldwide due to the pandemic of obesity. Obesity, impaired glucose metabolism, high blood pressure and atherogenic dyslipidemia are risk factors for MASLD. Therefore, insulin resistance may be closely associated with the development and progression of MASLD. Hepatic entry of increased fatty acids released from adipose tissue, increase in fatty acid synthesis and reduced fatty acid oxidation in the liver and hepatic overproduction of triglyceride-rich lipoproteins may induce the development of MASLD. Since insulin resistance also induces atherosclerosis, the leading cause for death in MASLD patients is cardiovascular disease. Considering that the development of cardiovascular diseases determines the prognosis of MASLD patients, the therapeutic interventions for MASLD should reduce body weight and improve coronary risk factors, in addition to an improving in liver function. Lifestyle modifications, such as improved diet and increased exercise, and surgical interventions, such as bariatric surgery and intragastric balloons, have shown to improve MASLD by reducing body weight. Sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to improve coronary risk factors and to suppress the occurrence of cardiovascular diseases. Both SGLT2i and GLP-1 have been reported to improve liver enzymes, hepatic steatosis and fibrosis. We recently reported that the selective peroxisome proliferator-activated receptor-alpha (PPARα) modulator pemafibrate improved liver function. PPARα agonists have multiple anti-atherogenic properties. Here, we consider the pathophysiology of MASLD and the mechanisms of action of such drugs and whether such drugs and the combination therapy of such drugs could be the treatments for MASLD.

Clinical, Hematological, Biochemical and Radiological Characteristics for Patients With Splenic Infarction: Case Series With Literature Review.

Background: Splenic infarction is a frequently missed diagnosis in acute clinical conditions and is often under-diagnosed due to the lack of high-quality evidence on pathophysiology of splenic infarction. Due to the scarcity of such evidence, no consensus guidelines regarding the diagnostic approach and management of patients with splenic infarction exist. Most of published articles on splenic infarction are case reports and there was no systematic review on splenic infarction. Methods: We conducted a retrospective analysis of all radiologically confirmed cases of splenic infarction patients with any history of admission at National Center for Global Health and Medicine Kohnodai Hospital, from 2014 to 2020. Further, to understand the pathophysiology that causes splenic infarction, we searched the literatures on splenic infarction. Results: We found 18 patients with splenic infarction. The average age was 78 years, and about half of patients had abdominal pain; however, the other half did not have abdominal pain. One-third of patients with splenic infarction died. Leukocytosis with neutrophilia, a decrease of lymphocytes, anemia, hypoalbuminemia, and liver dysfunction were observed. Fibrinogen was decreased and D-dimer was remarkably elevated. Lactate dehydrogenase (LDH) and C-reactive protein (CRP) were remarkably increased. Six patients (33.3%) had cancer, four patients (22.2%) had atrial fibrillation, and four patients (22.2%) had infection. We found 466 case reports on splenic infarction published from 1975 to 2021. Recently, the number of case reports on splenic infarction due to infection, especially, coronavirus disease 2019 (COVID-19), has been remarkably increasing. Furthermore, we found that leukocytosis, a decrease of lymphocytes, elongated activated partial thromboplastin time, decrease of fibrinogen, liver dysfunction, elevation of LDH and blood urea nitrogen can be the prognosis predicting factors for patients with splenic infarction. Conclusion: Our study elucidated clinical, hematological, biochemical and radiological characteristics for patients with splenic infarction. We newly found significant differences in blood cell counts, coagulation markers, transaminases, LDH and blood urea nitrogen between patients who died and those who survived, suggesting that these parameters can be the prognosis predicting factors for splenic infarction. Further, our systematic review on case reports about splenic infarction showed the etiology of splenic infarction and the trend of the causative diseases.

Use of biologics for systemic sclerosis and systemic sclerosis-associated interstitial lung disease: Information from a Japanese hospital claims database.

OBJECTIVES: Limited information is available on the use of biologics in patients with systemic sclerosis (SSc) or SSc-associated interstitial lung disease (SSc-ILD) in Japan. The types of biologics, treatment duration, treatment prior to biologics, concomitant treatment, and characteristics of patients receiving biologics were investigated. METHODS: We used a Japanese hospital claims database provided by Medical Data Vision Co. (2008-2021). RESULTS: In the database, 1186 of 34,207 SSc patients (3.5%) and 620 of 12,303 SSc-ILD patients (5.0%) received anti-interleukin-6 (anti-IL-6) drugs, anti-tumour necrosis factor (anti-TNF) drugs, abatacept, or rituximab. The most common were anti-IL-6 drugs [used in 35.5% of SSc patients and 38.5% of SSc-ILD patients (tocilizumab, 34.5% and 36.6%)], followed by anti-TNF drugs [31.3% and 26.5% (etanercept, 10.5% and 9.0%; others, <8%)], abatacept (17.5% and 20.6%), and rituximab (15.7% and 14.4%). Among SSc and SSc-ILD patients treated with anti-IL-6 drugs, anti-TNF drugs, or abatacept, the most common immunosuppressive drugs prior to initiation of biologics were methotrexate and tacrolimus. Approximately half of patients receiving anti-IL-6 drugs, anti-TNF drugs, or abatacept continued treatment beyond 1 year. CONCLUSIONS: Our study indicates that off-label biologics have been used in a certain number of SSc or SSc-ILD patients in Japan, with tocilizumab the most common.

Association between anti-complement factor H antibodies and renal outcome in primary membranous nephropathy.

AIMS: The complement factor H (CFH) is a regulator for the alternative complement pathway. The prevalence and roles of anti-CFH antibodies in the clinical outcome of primary membranous nephropathy (MN) patients remain unclear. MATERIALS AND METHODS: A total of 106 biopsy-proven kidney disease patients and 18 healthy controls were retrospectively investigated in this study. 36 patients had primary MN and 70 patients were diseased controls (31 minimal change nephrotic syndrome (MCNS), 19 rapidly progressive glomerulonephritis (RPGN), and 20 IgA glomerulonephritis (IgAGN)). Serum anti-CFH antibody titers were measured by enzyme-linked immunosorbent assay. RESULTS: 77.8% of MN patients were positive for anti-CFH antibodies. However, only 27.1% of diseased control patients and 5.6% of healthy controls were positive for anti-CFH antibodies. Moreover, median anti-CFH antibody titers were significantly higher in MN patients (4.69 AU/mL) than in diseased control patients (MCNS patients (0 AU/mL, p < 0.01), RPGN patients (0 AU/mL, p < 0.05), IgAGN patients (0 AU/mL, p < 0.01)), and healthy controls (0 AU/mL, p < 0.01). Anti-CFH antibody titer was selected as an independent unfavorable predictor of renal dysfunction by Cox proportional hazards analysis. CONCLUSION: These data suggest that anti-CFH antibodies may be involved in the deterioration of renal function in primary MN.

Steroid-sensitive recurrent mesangial proliferative glomerulonephritis with monoclonal IgG deposits.

Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMID) is a rare kidney disease. The predominant pathological finding of PGNMID is the presence of monoclonal Ig deposits on the glomerular basement membrane (GBM). However, there is some variation in deposition pattern in this kidney disease. We report a case of steroid-sensitive recurrent mesangial proliferative type of PGNMID. A 40-year-old female noticed lower leg pitting edema and polyuria. Approximately 10 days prior to the first clinic visit, she was diagnosed with nephrotic syndrome based on the laboratory data of urine and blood. Immunological and hematological examination revealed no abnormality. However, kidney biopsy specimens showed mild mesangial cell proliferation and mesangial matrix accumulation on light microscopic findings. Regarding immunofluorescence staining, granular deposits of IgG, C1q, and ß1c were observed on GBM and mesangial area. Granular deposits of IgG3 and λ were also observed on GBM and mesangial area. Moreover, negative results were obtained for the phospholipase A2 receptor antibody and thrombospondin type-1 domain-containing 7A. Electron microscopy revealed highly electron dense deposits mainly in the mesangial region. Kidney biopsy showed mesangial proliferative glomerulonephritis characterized by monoclonal Ig deposition of IgG3/λ. Steroid therapy was initiated, and complete remission was achieved on day 36. After the discontinuation of steroid therapy, proteinuria recurred and second kidney biopsy findings were almost similar to the first biopsy. However, complete remission was achieved with steroid therapy. This is a rare recurrent case of steroid-sensitive PGNMID. The pathological feature of this case was mesangial proliferative glomerulonephritis with Ig deposition of IgG3/λ.

Role and expression of non-classical human leukocyte antigen-G in renal transplanted allografts.

BACKGROUND: The non-classical class I molecule human leukocyte antigen-G (HLA-G) has great potential to modulate the immune response. However, the mechanism underlying HLA-G induction remains unknown. Therefore, this study aimed to determine the factors that induce HLA-G expression on proximal tubular epithelial cells (pTECs) in renal transplanted allografts in vivo and in vitro. METHODS: This study included 40 adult Japanese patients with renal allografts (35 and five patients with kidneys from living and deceased donors, respectively) who survived for at least 1 year. We evaluated HLA-G1/5 expression using an immunofluorescence method and investigated the induction of HLA-G expression in primary cultured human pTECs by cytokines and immunosuppressants. RESULTS: The HLA-G expression was identified in the perinuclear region or on the basement membrane of pTECs of renal biopsy tissue in 12 (30%) of 40 patients at 2-4 weeks and at 1 year following transplantation. A reduction of 30% in the estimated glomerular filtration rate was lower in the HLA-G-positive group than that of the negative group (p = 0.016). Cox proportional hazard models also demonstrated that HLA-G1/5 expression on pTECs was an independent predictor of improved renal allograft function (hazard ratio, 0.189; 95% CI 0.041-0.850, p = 0.030). Interferon-beta was the most powerful inducer of HLA-G expression in vitro, whereas the immunosuppressants everolimus, tacrolimus, cyclosporin, and dexamethasone did not induce any expression. CONCLUSION: Unlike immunosuppressants, acquired HLA-G expression might confer long-term renal preservation effects in renal transplanted allografts.

DNA damage in human glomerular endothelial cells induces nodular glomerulosclerosis via an ATR and ANXA2 pathway.

Collagen type VI (COL6) deposition occurs in various glomerular diseases, causing serious pathological damage like nodular lesions. However, the mechanisms underlying the deposition of COL6 remain unclear. In renal biopsy samples, immunohistochemical analyses revealed that COL6 and phosphorylated histone H2AX (γ-H2AX), a DNA damage marker, were detected mainly in diabetic nodular glomerulosclerosis, in which the γ-H2AX-positive area was identified as the independent factor significantly associated with the COL6-positive area (ß: 0.539, t = 2.668). In in vitro studies, COL6 secretion from human renal glomerular endothelial cells (HRGECs) was assessed by measuring the decrease in the cytoplasmic COL6-positive cells and an increase in the amount of COL6 in the culture medium. Mitomycin C (MMc) treatment of HRGECs increased the number of γ-H2AX-positive cells and COL6 secretion, which were suppressed by a specific inhibitor of ataxia telangiectasia and Rad3-related (ATR). MMc-induced COL6 secretion was also suppressed by Annexin A2 (ANXA2) siRNA transfection. Moreover, the inhibition of ATR activity did not induce any extra suppression in the MMc-induced COL6 secretion by ANXA2 siRNA transfected cells. These results confirm that nodular glomerulosclerosis partially results from DNA damage in the glomerulus and that DNA damage-induced COL6 secretion from HRGECs occurs through an ATR and ANXA2-mediated pathway.

Circulating CTRP9 correlates with the prevention of aortic calcification in renal allograft recipients.

BACKGROUND: Cardiovascular disease (CVD) due to atherosclerosis is a major cause of death in renal allograft recipients. Recently, C1q/TNF-α related protein-9 (CTRP9), which is a paralog of adiponectin (ADPN), has been suggested to be related to the prevention of atherosclerosis and the occurrence of CVD, but this relationship has not been confirmed in renal allograft recipients. SUBJECTS AND METHODS: The relationships among the serum CTRP9 concentration, serum ADPN concentration, and vascular calcification were investigated in 50 kidney transplantation recipients at our hospital. Calcification of the abdominal aorta was evaluated according to the aortic calcification area index (ACAI) calculated from CT images. Changes in the serum CTRP9 and ADPN fractions and ACAI were examined for 8 years. In addition, the expression of CTRP9 and ADPN and their respective receptors AdipoR1 and R2 in muscular arteries of the kidney was examined by immunofluorescence. RESULTS: In renal allograft recipients, the serum CTRP9 concentration at the start of the observation was not significant correlated with eGFR or serum high-molecular-weight (HMW)-ADPN concentration (rS = -0.009, p = 0.950; rS = -0.226, p = 0.114, respectively). However, the change in the serum CTRP9 concentration was positively correlated with the change in the serum HMW-ADPN concentration (rS = 0.315, p = 0.026) and negatively correlated with the change in ACAI (rS = -0.367, p = 0.009). Multiple regression analysis revealed that the serum HMW-ADPN concentration was a significant positive factor for the change in the serum CTRP9 concentration. Moreover, for ACAI, an increase in the serum CTRP9 concentration was an improving factor, but aging was an exacerbating factor. Furthermore, colocalization of CTRP9 and AdipoR1 was noted in the luminal side of intra-renal arterial intima. CONCLUSION: In renal allograft recipients, both CTRP9 and HMW-ADPN were suggested to prevent the progression of aortic calcification through AdipoR1.

High molecular weight adiponectin inhibits vascular calcification in renal allograft recipients.

BACKGROUND: Adiponectin (ADPN) prevents the development/recurrence of cardiovascular events via its anti-atherogenic effects. However, few long-term studies have examined the changes in serum ADPN levels and arterial calcification seen in renal allograft recipients. SUBJECTS AND METHODS: The effects of the serum ADPN level on arterial calcification were examined in 51 Japanese renal allograft recipients. Abdominal aorta calcification was evaluated on computed tomography using the aortic calcification area index (ACAI). The change in the ACAI and serum high-molecular-weight (HMW)-ADPN fractions were studied over an 8-year period. The arterial expression of ADPN, ADPN receptors (AdipoR)1 and 2, and T-cadherin (cadherin-13) were also examined by immunohistochemistry. RESULTS: The change in the ACAI were grouped into quartiles and compared with the alterations in the serum levels of each ADPN fraction over an 8-year period. The change in the ACAI was much lower in the patients with highly elevated HMW-ADPN levels.Multiple regression analysis demonstrated that an advanced age at transplant and a history of cardiovascular complications were associated with an increased change in the ACAI, while higher HMW-ADPN concentrations were associated with improvements in the ACAI. Serum HDL-C level was also identified as a positive factor to increase serum HMW-ADPN level.In immunohistochemical examinations, ADPN was detected on CD31-positive arterial endothelial cells from renal allograft biopsy samples. ADPN co-localized with T-cadherin and AdipoR1, but only partially co-localized with AdipoR2. CONCLUSION: Both HMW-ADPN and HDL-C might inhibit the progression of vascular calcification by promoting ADPN binding to vascular endothelial cells via T-cadherin and AdipoR in Japanese renal allograft recipients.

Circulating and renal expression of HLA-G prevented chronic renal allograft dysfunction in Japanese recipients.

BACKGROUND: Although the risk of acute rejection has been studied in renal transplanted patients, there is little data about the long-term renal survival effects of non-classical human leukocyte antigen class I (HLA-G) in Japanese patients. METHOD: We investigated the changes in the estimated glomerular filtration rate (eGFR) for Japanese, and factors affecting the eGFR in 141 adult Japanese subjects whose allografts had survived for at least 1 year. Clinical background data, gender, HLA matching status, the total ischemic time, ABO incompatibility, immunosuppressive therapy, and the serum soluble(s) HLA-G5 level were examined. In addition, renal biopsy specimens from 32 cases, which were obtained before, or 2-4 weeks or one year after the transplant were also evaluated for HLA-G1/5 expression using monoclonal anti-HLA-G antibodies (clone 87G or 4H84). RESULTS: The rates of change per year in the median eGFR (ΔeGFR) and sHLA-G5 were -1.5 ml/min/1.73 m2/year and 11.8 ng/ml, respectively. A positive correlation was detected between the ΔeGFR and sHLA-G5 (r = 0.188, p = 0.025). In multivariate regression analysis, sHLA-G5 and HLA-matching were significant predictors of an improvement in eGFR (beta for sHLA-G: 0.374, p = 0.009; beta for mismatching: -1.135, p = 0.045). The renal tubular epithelial cells (TEC) in 11 cases showed a perinuclear HLA-G1/5 expression after renal transplantation. The renal HLA-G1/5-positive patients displayed much better ΔeGFR (p < 0.05). In conclusion, the sHLA-G5 level and HLA matching status are independent predictors of renal allograft function, as determined by the ΔeGFR, in Japanese patients. HLA-G1/5 was also detected on TEC in the patients with favorable renal function.

The long-term outcomes of hepatitis C virus core antigen-positive Japanese renal allograft recipients.

BACKGROUND: The impact of hepatitis C virus (HCV) infections on patient long-term survival after renal transplants is unclear. METHOD: To clarify the long-term outcomes of Japanese renal allograft recipients with HCV infections, we studied the cases of 187 patients (118 males and 69 females; 155 living donor cases, and 32 deceased donor cases; median follow-up period: 250 months) who underwent an initial renal transplant at Kanazawa Medical University from 1974 onwards. RESULT: In this cohort, 35 patients (18.7%) were HCV core antigen (Ag)-positive, and 13 of them (37.1%) died (due to liver cirrhosis (4 cases), hepatocellular carcinoma (1 case), fibrosing cholestatic hepatitis due to HCV (1 case), and infections complicated with chronic hepatitis (6 cases)). However, only 14 of the 145 (9.7%) recipients died in the HCV-Ag/HCV antibody (Ab)-negative group. The Kaplan-Meier life table method indicated that the HCV-infected group exhibited significantly lower patient and death-censored allograft survival rates (log-rank test; patient survival: Chi-square: 11.2, p = 0.004; graft survival: Chi-square: 25.7, p < 0.001). The survival rate of the HCV-Ag-positive recipients decreased rapidly at 240 months after the renal transplant procedure. In addition, a Cox proportional hazards model indicated that positivity for the HCV-Ag was the most important independent risk factor for post-renal transplant survival and allograft function [survival: hazard ratio (HR) 3.93 (1.54-10.03), p = 0.004; graft function: HR 2.09 (1.14-3.81), p = 0.016]. CONCLUSION: HCV infection is a harmful risk factor for patient survival (especially at ≥20 years post-renal transplant) and renal allograft function in allograft recipients.

The impact of PNPLA3 and JAZF1 on hepatocellular carcinoma in non-viral hepatitis patients with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is an established independent risk factor for hepatocellular carcinoma (HCC). T2DM is associated with non-alcoholic steatohepatitis (NASH), which is a major cause of non-HBV and non-HCV-related HCC; nevertheless, it has been difficult to identify those patients with T2DM who have a high risk of developing HCC. The aim of this study was to identify genetic determinants that predispose T2DM patients to HCC by genotyping T2DM susceptibility loci and PNPLA3. METHODS: We recruited 389 patients with T2DM who satisfied the following three criteria: negative for HBs-Ag and anti-HCV Ab, alcohol intake <60 g/day, and history of T2DM >10 years. These patients were divided into two groups: T2DM patients with HCC (DM-HCC, n = 59) or those without HCC (DM-non-HCC, n = 330). We genotyped 51 single-nucleotide polymorphisms (SNPs) previously reported as T2DM or NASH susceptibility loci (PNPLA3) compared between the DM-HCC and DM-non-HCC groups with regard to allele frequencies at each SNP. RESULTS: The SNP rs738409 located in PNPLA3 was the greatest risk factor associated with HCC. The frequency of the PNPLA3 G allele was significantly higher among DM-HCC individuals than DM-non-HCC individuals (OR 2.53, p = 1.05 × 10(-5)). Among individuals homozygous for the PNPLA3 G allele (n = 115), the frequency of the JAZF1 rs864745 G allele was significantly higher among DM-HCC individuals than DM-non-HCC individuals (OR 3.44, p = 0.0002). CONCLUSIONS: PNPLA3 and JAZF1 were associated with non-HBV and non-HCV-related HCC development among Japanese patients with T2DM.

A case of IgG4-related kidney disease complicated by eosinophilic lung disease.

IgG4-related disease is a systemic chronic inflammatory disorder characterized by a high blood level of IgG4 and the organ injuries by marked infiltration of IgG4-positive plasma cells and fibrosis. A 71-year-old male was hospitalized for a cough, malaise and anorexia. IgG4-related disease was suspected due to marked elevation of the serum IgG4 level. However, on lung biopsy, only eosinophil infiltration was demonstrated with no plasma cell infiltration. Otherwise abdominal contrast-enhanced CT showed mild enlargement of the bilateral kidneys and many differed contrasted areas and FDG PET-CT. Moreover, renal biopsy specimens showed typical tubulointerstitial nephritis with a large number of IgG4-positive plasma cells infiltration (the IgG4/IgG-positive cell rate, 89 %) and fibrosis. We diagnosed this patient as typical IgG4-related kidney disease. He was treated by the moderate dose of prednisolone (0.8 mg/kg/day) alone, and showed prompt response in the clinical condition, and both the lung and kidney lesions. In this case, it was useful for diagnosis of IgG4-related diseases to evaluate an image such as abdominal contrast-enhanced CT and FDG PET-CT. Our case might be one of the possible patterns of IgG4-related lung diseases. In addition, we thought that there might be an association between hypereosinophilia and IgG4-related kidney disease.

Clinicopathological characteristics of M-type phospholipase A2 receptor (PLA2R)-related membranous nephropathy in Japanese.

BACKGROUND: Recent studies have suggested that assessments of serum antibodies against M-type phospholipase A2 receptor (PLA2R) and the glomerular expression of PLA2R antigen in biopsy specimens are useful for the diagnosis of primary membranous nephropathy (MN). In this study, we assessed both of them and investigated the clinicopathological characteristics of PLA2R-related Japanese MN. METHODS: We retrospectively enrolled 22 primary and 3 secondary Japanese patients whose serum samples and renal specimens were collected before treatment. According to the findings of serum antibodies and antigen in glomeruli, the primary MN patients were classified into PLA2R-related or -unrelated MN. We compared their clinicopathological findings, including IgG subclass staining, and electron microscopic findings, and evaluated the predictors of proteinuria remission. RESULTS: In primary MN, 16 patients (73 %) were classified into the PLA2R-related group, and 6 patients into the PLA2R-unrelated group. There was no significant difference in baseline laboratory data and electron microscopic findings, except for eGFR and serum IgG levels. IgG4-dominant deposition was more common in the related group (63 vs. 0 %). The 10 PLA2R-related patients with dominant IgG4 deposition had a lower rate and prolonged time in remission compared with the 6 PLA2R-related patients with non-dominant IgG4 (log-rank, p = 0.032). Furthermore, dominant IgG4 deposition was an unfavorable predictor of remission by multivariable Cox proportional hazard analysis. CONCLUSIONS: Assessments of both serum PLA2R antibodies and PLA2R antigen in glomeruli were more sensitive for the diagnosis of PLA2R-related MN, and among affected Japanese patients, those with dominant IgG4 deposition had worse clinical outcomes.